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    Assessing the risk for major injuries in equestrian sports 

    Krüger, Lara; Hohberg, Maike; Lehmann, Wolfgang; Dresing, Klaus
    BMJ Open Sport & Exercise Medicine 2018; 4(1): Art. e000408
    Background/aim: Horse riding is a popular sport, which bears the risk of serious injuries. This study aims to assess whether individual factors influence the risk to sustain major injuries. Methods: Retrospective data were collected from all equine-related accidents at a German Level I Trauma Centre between 2004 and 2014. Logistic regression was used to identify the risk factors for major injures. Results: 770 patients were included (87.9% females). Falling off the horse (67.7%) and being kicked by the horse (16.5%) were the two main injury mechanisms. Men and individuals of higher age showed higher odds for all tested parameters of serious injury. Patients falling off a horse had higher odds for being treated as inpatients, whereas patients who were kicked had higher odds for a surgical therapy (OR 1.7) and intensive care unit/intermediate care unit (ICU/IMC) treatment (OR 1.2). The head was the body region most often injured (32.6%) and operated (32.9%). Patients with head injuries had the highest odds for being hospitalised (OR 6.13). Head or trunk injuries lead to the highest odds for an ICU/IMC treatment (head: OR 4.37; trunk: OR 2.47). Upper and lower limb injuries showed the highest odds for a surgical therapy (upper limb: OR 2.61; lower limb: OR 1.7). Conclusion: Risk prevention programmes should include older individuals and males as target groups. Thus a rethinking of the overall risk assessment is necessary. Not only horseback riding itself, but also handling a horse bears a relevant risk for major injuries. Serious head injures remain frequent, serious and an important issue to be handled in equestrians sports.
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    Modulation of Chemokine- and Adhesion-Molecule Gene Expression and Recruitment of Neutrophil Granulocytes in Rat and Mouse Liver after a Single Gadolinium Chloride or Zymosan Treatment 

    Ahmad, Shakil; Ramadori, Giuliano; Moriconi, Federico
    International Journal of Molecular Sciences 2018; 19(12): Art. 3891
    Kupffer cells are professional phagocytes of the liver clearing bacteria from portal blood. Their clearance capacity, however, can be overwhelmed, transforming them into critical mediators of hepatic-injury. We investigated the consequences of selective Kupffer cell-overload by intraperitoneally administering pyrogen-free gadolinium chloride (GdCl3) or Zymosan into rats and into endotoxin-resistant mice (C3H/HeJ). The number of myeloperoxidase-positive (MPO+) cells increased at 3 h mainly around the portal vessel after both GdCl3 and Zymosan treatment. Simultaneously, GdCl3 administration reduced detectability of ED-1+ (but not ED-2) cells near the portal vessel. Serum chemokine (C-X-C motif) ligand 1 (CXCL-1), CXCL-2 and chemokine (C-C motif) ligand 2 (CCL-2) showed a peak at 3 h after both treatment regimens although at a higher extent after Zymosan administration. Accordingly, CXCL-1, CXCL-5 and CCL-2 gene expression in the liver was up-regulated after GdCl3 treatment at 3 h. After Zymosan administration a significant up-regulation of CXCL-1, CXCL-2, CXCL-10, CCL-2, CCL-3 and CCL-20 gene expression in liver at 3 h was observed. After Zymosan administration intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) gene expression was up-regulated in rat liver tissue. In C3H/HeJ mice both treatment regimens up-regulated CCL-2 and ICAM-1 gene expression after 3 h and down-regulated platelet endothelial cell adhesion molecule 1 (PECAM-1) gene expression. In conclusion, phagocytosis overload of Kupffer cells causes induction of several CXC, CC-chemokines, upregulation of “positive” adhesion molecule gene expression, down-regulation of the “negative” adhesion molecule PECAM-1 and a recruitment of neutrophil granulocytes in the portal area of the liver of treated rats and mice mainly in close contact to the liver macrophages.
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    Cognitive Control Over Visual Motion Processing – Are Children With ADHD Especially Compromised? A Pilot Study of Flanker Task Event-Related Potentials 

    Lange-Malecki, Bettina; Treue, Stefan; Rothenberger, Aribert; Albrecht, Björn
    Frontiers in Human Neuroscience 2018; 12: Art. 491
    Performance deficits and diminished brain activity during cognitive control and error processing are frequently reported in attention deficit/hyperactivity disorder (ADHD), indicating a “top-down” deficit in executive attention. So far, these findings are almost exclusively based on the processing of static visual forms, neglecting the importance of visual motion processing in everyday life as well as important attentional and neuroanatomical differences between processing static forms and visual motion. For the current study, we contrasted performance and electrophysiological parameters associated with cognitive control from two Flanker-Tasks using static stimuli and moving random dot patterns. Behavioral data and event-related potentials were recorded from 16 boys with ADHD (combined type) and 26 controls (aged 8–15 years). The ADHD group showed less accuracy especially for moving stimuli, and prolonged response times for both stimulus types. Analyses of electrophysiological parameters of cognitive control revealed trends for diminished N2-enhancements and smaller error-negativities (indicating medium effect sizes), and we detected significantly lower error positivities (large effect sizes) compared to controls, similarly for both static and moving stimuli. Taken together, the study supports evidence that motion processing is not fully developed in childhood and that the cognitive control deficit in ADHD is of higher order and independent of stimulus type.
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    Workshop on Germ Cells 

    Dosch, Roland
    Frontiers in Cell and Developmental Biology 2018; 6: Art. 157
    Germ cell research in vertebrates has traditionally been challenging, but recent breakthroughs have overcome technical difficulties, demonstrating and expanding the power of the zebrafish experimental system for their analysis in vivo. Exploiting the transparency of the zebrafish embryo, germ cell migration was the first topic that moved the germ cells of this organism into the spotlight of modern research. In recent years, research on teleost germ cells has expanded into additional fields, manifested by a session dedicated to this cell type at the European Zebrafish PI meeting in Trento.
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    Prophylactic Palmitoylethanolamide Prolongs Survival and Decreases Detrimental Inflammation in Aged Mice With Bacterial Meningitis 

    Heide, Ev Christin; Bindila, Laura; Post, Julia Maria; Malzahn, Dörthe; Lutz, Beat; Seele, Jana; Nau, Roland; Ribes, Sandra
    Frontiers in Immunology 2018; 9: Art. 2671
    Easy-to-achieve interventions to promote healthy longevity are desired to diminish the incidence and severity of infections, as well as associated disability upon recovery. The dietary supplement palmitoylethanolamide (PEA) exerts anti-inflammatory and neuroprotective properties. Here, we investigated the effect of prophylactic PEA on the early immune response, clinical course, and survival of old mice after intracerebral E. coli K1 infection. Nineteen-month-old wild type mice were treated intraperitoneally with two doses of either 0.1 mg PEA/kg in 250 μl vehicle solution (n = 19) or with 250 μl vehicle solution only as controls (n = 19), 12 h and 30 min prior to intracerebral E. coli K1 infection. The intraperitoneal route was chosen to reduce distress in mice and to ensure exact dosing. Survival time, bacterial loads in cerebellum, blood, spleen, liver, and microglia counts and activation scores in the brain were evaluated. We measured the levels of IL-1β, IL-6, MIP-1α, and CXCL1 in cerebellum and spleen, as well as of bioactive lipids in serum in PEA- and vehicle-treated animals 24 h after infection. In the absence of antibiotic therapy, the median survival time of PEA-pre-treated infected mice was prolonged by 18 h compared to mice of the vehicle-pre-treated infected group (P = 0.031). PEA prophylaxis delayed the onset of clinical symptoms (P = 0.037). This protective effect was associated with lower bacterial loads in the spleen, liver, and blood compared to those of vehicle-injected animals (P ≤ 0.037). PEA-pre-treated animals showed diminished levels of pro-inflammatory cytokines and chemokines in spleen 24 h after infection, as well as reduced serum concentrations of arachidonic acid and of one of its metabolites, 20-hydroxyeicosatetraenoic acid. In the brain, prophylactic PEA tended to reduce bacterial titers and attenuated microglial activation in aged infected animals (P = 0.042). Our findings suggest that prophylactic PEA can counteract infection associated detrimental responses in old animals. Accordingly, PEA treatment slowed the onset of infection symptoms and prolonged the survival of old infected mice. In a clinical setting, prophylactic administration of PEA might extend the potential therapeutic window where antibiotic therapy can be initiated to rescue elderly patients.
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    Pantoprazole Does not Affect Serum Trough Levels of Tacrolimus and Everolimus in Liver Transplant Recipients 

    Bremer, Sebastian C. B.; Reinhardt, Lars; Sobotta, Michael; Hasselluhn, Marie C.; Lorf, Thomas; Ellenrieder, Volker; Schwörer, Harald
    Frontiers in Medicine 2018; 5: Art. 320
    Background: Liver transplant recipients are frequently treated with proton pump inhibitors. Drug interactions have been described especially with respect to omeprazole. Due to the lower binding capacity of pantoprazole to CYP2C19 this drug became preferred and became the most used proton pump inhibitor in Germany. The data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients a very scarce. Methods: The authors performed a single center analysis in liver transplant recipients on the effect of pantoprazole on the serum trough levels of different immunosuppressants. The trough levels were compared over a period of 1 year before and after start or stop of a continuous oral co-administration of 40 mg pantoprazole once daily. Results: The serum trough levels of tacrolimus (n = 30), everolimus (n = 7), or sirolimus (n = 3) remain constant during an observation period of at least 1 year before and after co-administration of pantoprazole. None of the included patients needed a change of dosage of the observed immunosuppressants during the observation period. Conclusions: The oral co-administration of pantoprazole is safe in immunosuppressed liver transplant recipients according to the serum trough levels of tacrolimus, everolimus, and sirolimus. This analysis provides first data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients.
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    Modifications of Surgical Suction Tip Geometry for Flow Optimisation: Influence on Suction-Induced Noise Pollution 

    Friedrich, M. G.; Tirilomis, T.; Kollmeier, J. M.; Wang, Y.; Hanekop, G. G.
    Surgery Research and Practice 2018; 2018 p.1-8
    Introduction. Suction devices for clearing the surgical field are among the most commonly used tools of every surgeon because a better view of the surgical field is essential. Forced suction may produce disturbingly loud noise, which acts as a nonnegligible stressor. Especially, in emergency situations with heavy bleeding, this loud noise has been described as an impeding factor in the medical decision-making process. In addition, there are reports of inner ear damage in patients due to suction noises during operations in the head area. These problems have not been solved yet. The purpose of this study was to analyse flow-dependent suction noise effects of different surgical suction tips. Furthermore, we developed design improvements to these devices. Methods. We compared five different geometries of suction tips using an in vitro standardised setup. Two commercially available standard suction tips were compared to three adapted new devices regarding their flow-dependent (10–2000 mL/min) noise emission (dB, weighting filter (A), distance 10 cm) and acoustic quality of resulting noises (Hamilton fast Fourier analysis) during active suction at the liquid-air boundary. Noise maps at different flow rates were created for all five suction devices, and the proportion of extracted air was measured. The geometries of the three custom-made suction tips (new models 1, 2, and 3) were designed considering the insights after determining the key characteristics of the two standard suction models. Results. The geometry of a suction device tip has significant impact on its noise emission. For the standard models, the frequency spectrum at higher flow rates significantly changes to high-frequency noise patterns (>3 kHz). A number of small side holes designed to prevent tissue adhesion lead to increased levels of high-frequency noise. Due to modifications of the tip geometry in our new models, we are able to achieve a highly significant reduction of noise level at low flow rates (new model 2 vs. standard models ) and also the acoustic quality improved. Additionally, we attain a highly significant reduction of secondary air intake (new model 2 vs. the other models ). Conclusion. Improving flow-relevant features of the geometry of suction heads is a suitable way to reduce noise emissions. Optimized suction tips are significantly quieter. This may help us to reduce noise-induced hearing damage in patients as well as stress of medical staff during surgery and should lead to quieter operation theatres overall. Furthermore, the turbulence reduction and reduced secondary air intake during the suction process are expected to result in protective effects on the collected blood and thus could improve the quality of autologous blood retransfusions. We are on the way to evaluate potential benefits.
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    CD8+-T Cells With Specificity for a Model Antigen in Cardiomyocytes Can Become Activated After Transverse Aortic Constriction but Do Not Accelerate Progression to Heart Failure 

    Gröschel, Carina; Sasse, André; Monecke, Sebastian; Röhrborn, Charlotte; Elsner, Leslie; Didié, Michael; Reupke, Verena; Bunt, Gertrude; Lichtman, Andrew H.; Toischer, Karl; et al.
    Zimmermann, Wolfram-HubertusHasenfuß, GerdDressel, Ralf
    Frontiers in Immunology 2018; 9: Art. 2665
    Heart failure due to pressure overload is frequently associated with inflammation. In addition to inflammatory responses of the innate immune system, autoimmune reactions of the adaptive immune system appear to be triggered in subgroups of patients with heart failure as demonstrated by the presence of autoantibodies against myocardial antigens. Moreover, T cell-deficient and T cell-depleted mice have been reported to be protected from heart failure induced by transverse aortic constriction (TAC) and we have shown recently that CD4+-helper T cells with specificity for an antigen in cardiomyocytes accelerate TAC-induced heart failure. In this study, we set out to investigate the potential contribution of CD8+-cytotoxic T cells with specificity to a model antigen (ovalbumin, OVA) in cardiomyocytes to pressure overload-induced heart failure. In 78% of cMy-mOVA mice with cardiomyocyte-specific OVA expression, a low-grade OVA-specific cellular cytotoxicity was detected after TAC. Adoptive transfer of OVA-specific CD8+-T cells from T cell receptor transgenic OT-I mice before TAC did not increase the risk of OVA-specific autoimmunity in cMy-mOVA mice. After TAC, again 78% of the mice displayed an OVA-specific cytotoxicity with on average only a three-fold higher killing of OVA-expressing target cells. More CD8+ cells were present after TAC in the myocardium of cMy-mOVA mice with OT-I T cells (on average 17.5/mm2) than in mice that did not receive OVA-specific CD8+-T cells (3.6/mm2). However, the extent of fibrosis was similar in both groups. Functionally, as determined by echocardiography, the adoptive transfer of OVA-specific CD8+-T cells did not significantly accelerate the progression from hypertrophy to heart failure in cMy-mOVA mice. These findings argue therefore against a major impact of cytotoxic T cells with specificity for autoantigens of cardiomyocytes in pressure overload-induced heart failure.
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    Paths of femoral nerve catheters placed using ultrasound-guided in plane vs out of plane techniques 

    Büttner, Benedikt; Dracklé, Joschka; Kristof, Katalin; Hinz, José; Schwarz, Alexander; Bauer, Martin; Mansur, Ashham; Bergmann, Ingo
    Medicine 2018; 97(43): Art. e12958
    BACKGROUND: Continuous blockade of the femoral nerve is widely used for postoperative analgesia after hip surgery. It can be achieved by ultrasound-guided placement of a femoral nerve catheter via either the in plane (IP) or out of plane (OOP) technique. On the basis of postoperative radiographs, we evaluated the paths of femoral nerve catheters with respect to both techniques and its effect on postoperative analgesia. METHODS: Thirty-four patients were randomized to receive a radiopaque femoral nerve catheter via either the IP or OOP technique. The paths and tip position of the catheters were evaluated in postoperative frontal radiographs of the operated hip joint concerning a predefined target region and four neighboring regions. Pain scores were assessed using a numeric rating scale (0-10). RESULTS: Sixteen IP patients and 18 OOP patients were included in the study. The catheter path was radiographically evaluated in 13 IP patients and in 10 OOP patients. The catheter tips were located within the target region in 39% of the IP group and in 50% of the OOP group. The catheter tip was 0.00 cm [-3.80 to 3.84] and -1.19 cm [-12.27 to 0.00] (median [range]) from the target region in the OOP group and IP group, respectively (P = .045). Catheters flipped distally more often in the IP group (IP: 61.5%, OOP: 10.0%; P = .01). There were no marked differences in the pain scores of either group. CONCLUSION: Femoral nerve catheters inserted by the ultrasound-guided IP technique flip distally more frequently than catheters inserted by the OOP technique. Moreover, the distance between the catheter tip and the trunk of the femoral nerve is greater for IP catheters than for OOP catheters. Despite these findings, postoperative analgesia did not seem to differ between the 2 techniques.
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    Interlaboratory validation of cerebrospinal fluid α-synuclein quantification in the diagnosis of sporadic Creutzfeldt-Jakob disease 

    Kruse, Niels; Heslegrave, Amanda; Gupta, Vandana; Foiani, Martha; Villar-Piqué, Anna; Schmitz, Matthias; Lehmann, Sylvain; Teunissen, Charlotte; Blennow, Kaj; Zetterberg, Henrik; et al.
    Mollenhauer, BritZerr, IngaLlorens, Franc
    Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring 2018; 10 p.461-470
    ntroduction: Cerebrospinal fluid α-synuclein level is increased in sporadic Creutzfeldt-Jakob disease cases. However, the clinical value of this biomarker remains to be established. In this study, we have addressed the clinical validation parameters and the interlaboratory reproducibility by using an electrochemiluminescent assay. Methods: Cerebrospinal fluid α-synuclein was quantified in a total of 188 sporadic Creutzfeldt-Jakob disease and non-Creutzfeldt-Jakob-disease cases to determine sensitivity and specificity values and lot-to-lot variability. Two round robin tests with 70 additional cases were performed in six independent laboratories. Results: A sensitivity of 93% and a specificity of 96% were achieved in discriminating sporadic Creutzfeldt-Jakob disease. No differences were detected between lots. The mean interlaboratory coefficient of variation was 23%, and the intralaboratory coefficient of variations ranged 2.70%-11.39%. Overall, 97% of samples were correctly diagnosed. Discussion: The herein validated α-synuclein assay is robust, accurate, and reproducible in identifying Creutzfeldt-Jakob disease cases. Thus, it is ready for implementation in the clinical practice to support the diagnosis of Creutzfeldt-Jakob disease.
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    Glycoprotein NMB: a novel Alzheimer’s disease associated marker expressed in a subset of activated microglia 

    Hüttenrauch, Melanie; Ogorek, Isabella; Klafki, Hans; Otto, Markus; Stadelmann, Christine; Weggen, Sascha; Wiltfang, Jens; Wirths, Oliver
    Acta Neuropathologica Communications 2018; 6(1): Art. 108
    Alzheimer's disease (AD) is an irreversible, devastating neurodegenerative brain disorder characterized by the loss of neurons and subsequent cognitive decline. Despite considerable progress in the understanding of the pathophysiology of AD, the precise molecular mechanisms that cause the disease remain elusive. By now, there is ample evidence that activated microglia have a critical role in the initiation and progression of AD. The present study describes the identification of Glycoprotein nonmetastatic melanoma protein B (GPNMB) as a novel AD-related factor in both transgenic mice and sporadic AD patients by expression profiling, immunohistochemistry and ELISA measurements. We show that GPNMB levels increase in an age-dependent manner in transgenic AD models showing profound cerebral neuron loss and demonstrate that GPNMB co-localizes with a distinct population of IBA1-positive microglia cells that cluster around amyloid plaques. Our data further indicate that GPNMB is part of a microglia activation state that is only present under neurodegenerative conditions and that is characterized by the up-regulation of a subset of genes including TREM2, APOE and CST7. In agreement, we provide in vitro evidence that soluble Aβ has a direct effect on GPNMB expression in an immortalized microglia cell line. Importantly, we show for the first time that GPNMB is elevated in brain samples and cerebrospinal fluid (CSF) of sporadic AD patients when compared to non-demented controls.The current findings indicate that GPNMB represents a novel disease-associated marker that appears to play a role in the neuroinflammatory response of AD.
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    TMJ pathomorphology in patients with JIA-radiographic parameters for early diagnosis- 

    Klenke, Daniela; Quast, Anja; Prelog, Martina; Holl-Wieden, Annette; Riekert, Maximilian; Stellzig-Eisenhauer, Angelika; Meyer-Marcotty, Philipp
    Head & Face Medicine 2018; 14(15)
    BACKGROUND: Juvenile idiopathic arthritis (JIA) is often accompanied by pathomorphological changes to the temporomandibular joint (TMJ). By analyzing orthodontical orthopantomograms of JIA patients the aims of the study were a) classification of condyle changes, b) quantification of bony asymmetries of condylar destruction and c) detection of relationships between disease duration and TMJ-involvement. PATIENTS/METHODS: 46 caucasian JIA-patients (28 female; 18 male; < 16.0 years) were enrolled, each joint (n = 92) was morphologically assessed by means of orthopantomogram, quantitatively analysed and compared with duration of general disease. Condyle morphology was assessed using the Billiau scale for severity of destruction [1]. The quantitative analysis was based on ratios of condyle, ramus and mandible height. RESULTS: Patients were divided into groups (Group I - slightly affected, n = 36; Billiau severity 0-2; condyle findings: X-ray normal, condyle erosions, condylar flattening; Group II - severely affected, N = 10; Billiau severity 3-4; condyle findings: condylar flattenings and erosions, unilateral/bilateral complete loss of condyles), based on morphological analysis of condylar destruction. Duration of disease was significantly longer in Group II (8.9 ± 5.2 years) than in Group I (4.6 ± 4.7 years). Asymmetries of condyle, ramus and mandible height, quantitatively analysed by contralateral comparison, were significantly more marked in patients of Group II than of Group I. CONCLUSIONS: Orthopantomogram imaging can be used in orthodontics clinical routine to detect TMJ-pathologies and is an important reference for monitoring progression of JIA. Classification into severe and slightly affected TMJ is possible by analysis of condylar pathomorphology. An association between degree of destruction, extent of lower jaw asymmetry and disease duration is suggested by the results.
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    The transducer-like protein Tlp12 of Campylobacter jejuni is involved in glutamate and pyruvate chemotaxis 

    Lübke, Anastasia-Lisa; Minatelli, Sabrina; Riedel, Thomas; Lugert, Raimond; Schober, Isabel; Spröer, Cathrin; Overmann, Jörg; Groß, Uwe; Zautner, Andreas E.; Bohne, Wolfgang
    BMC Microbiology 2018; 18(111)
    BACKGROUND: Campylobacter jejuni is one of the most common bacterial causes of food-borne enteritis worldwide. Chemotaxis in C. jejuni is known to be critical for the successful colonization of the host and key for the adaptation of the microbial species to different host environments. In C. jejuni, chemotaxis is regulated by a complex interplay of 13 or even more different chemoreceptors, also known as transducer-like proteins (Tlps). Recently, a novel chemoreceptor gene, tlp12, was described and found to be present in 29.5% of the investigated C. jejuni strains. RESULTS: In this study, we present a functional analysis of Tlp12 with the aid of a tlp12 knockout mutant of the C. jejuni strain A17. Substrate specificity was investigated by capillary chemotaxis assays and revealed that Tlp12 plays an important role in chemotaxis towards glutamate and pyruvate. Moreover, the Δtlp12 mutant shows increased swarming motility in soft agar assays, an enhanced invasion rate into Caco-2 cells and an increased autoagglutination rate. The growth rate was slightly reduced in the Δtlp12 mutant. The identified phenotypes were in partial restored by complementation with the wild type gene. Tlp12-harboring C. jejuni strains display a strong association with chicken, whose excreta are known to contain high glutamate levels. CONCLUSIONS: TLP12 is a chemoreceptor for glutamate and pyruvate recognition. Deletion of tlp12 has an influence on distinct physiological features, such as growth rate, swarming motility, autoagglutination and invasiveness.
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    mully: An R Package to Create, Modify and Visualize Multilayered Graphs 

    Hammoud, Zaynab; Kramer, Frank
    Genes 2018; 9(11): Art. 519
    The modelling of complex biological networks such as pathways has been a necessity for scientists over the last decades. The study of these networks also imposes a need to investigate different aspects of nodes or edges within the networks, or other biomedical knowledge related to it. Our aim is to provide a generic modelling framework to integrate multiple pathway types and further knowledge sources influencing these networks. This framework is defined by a multi-layered model allowing automatic network transformations and documentation. By providing a tool that generates this model, we aim to facilitate the data integration, boost the reproducibility and increase the interoperability between different sources and databases in the field of pathways. We present mully R package that allows the user to create, modify and visualize graphs with multi-layers. The package is implemented with features to specifically handle multilayered graphs.
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    CA1 Neurons Acquire Rett Syndrome Phenotype After Brief Activation of Glutamatergic Receptors: Specific Role of mGluR1/5 

    Balakrishnan, Saju; Mironov, Sergej L.
    Frontiers in Cellular Neuroscience 2018; 12: Art. 363
    Rett syndrome (RTT) is a neurological disorder caused by the mutation of the X-linked MECP2 gene. The neurophysiological hallmark of the RTT phenotype is the hyperexcitability of neurons made responsible for frequent epileptic attacks in the patients. Increased excitability in RTT might stem from impaired glutamate handling in RTT and its long-term consequences that has not been examined quantitatively. We recently reported (Balakrishnan and Mironov, 2018a,b) that the RTT hippocampus consistently demonstrates repetitive glutamate transients that parallel the burst firing in the CA1 neurons. We aimed to examine how brief stimulation of specific types of ionotropic and metabotropic glutamate receptors (GluR) can modulate the neuronal phenotype. We imaged glutamate with a fluorescence sensor (iGluSnFr) expressed in CA1 neurons in hippocampal organotypic slices from wild-type (WT) and Mecp2-/y mice (RTT). The neuronal and synaptic activities were assessed by patch-clamp and calcium imaging. In both WT and RTT slices, activation of AMPA, kainate, and NMDA receptors for 30 s first enhanced neuronal activity that induced a global release of glutamate. After transient augmentation of excitability and ambient glutamate, they subsided. After wash out of the agonists for 10 min, WT slices recovered and demonstrated repetitive glutamate transients, whose pattern resembled those observed in naïve RTT slices. Hyperpolarization-activated (HCN) decreased and voltage-sensitive calcium channel (VSCC) currents increased. The effects were long-lasting and bigger in WT. We examined the role of mGluR1/5 in more detail. The effects of the agonist (S)-3,5-dihydroxyphenylglycine (DHPG) were the same as AMPA and NMDA and occluded by mGluR1/5 antagonists. Further modifications were examined using a non-stationary noise analysis of postsynaptic currents. The mean single channel current and their number at postsynapse increased after DHPG. We identified new channels as calcium-permeable AMPARs (CP-AMPAR). We then examined back-propagating potentials (bAPs) as a measure of postsynaptic integration. After bAPs, spontaneous afterdischarges were observed that lasted for ∼2 min and were potentiated by DHPG. The effects were occluded by intracellular CP-AMPAR blocker and did not change after NMDAR blockade. We propose that brief elevations in ambient glutamate (through brief excitation with GluR agonists) specifically activate mGluR1/5. This modifies CP-AMPAR, HCN, and calcium conductances and makes neurons hyperexcitable. Induced changes can be further supported by repetitive glutamate transients established and serve to persistently maintain the aberrant neuronal RTT phenotype in the hippocampus.
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    xial Tubule Junctions Activate Atrial Ca2+ Release Across Species 

    Brandenburg, Sören; Pawlowitz, Jan; Fakuade, Funsho E.; Kownatzki-Danger, Daniel; Kohl, Tobias; Mitronova, Gyuzel Y.; Scardigli, Marina; Neef, Jakob; Schmidt, Constanze; Wiedmann, Felix; et al.
    Pavone, Francesco S.Sacconi, LeonardoKutschka, IngoSossalla, SamuelMoser, TobiasVoigt, NielsLehnart, Stephan E.
    Frontiers in Physiology 2018; 9: Art. 1227
    Rationale: Recently, abundant axial tubule (AT) membrane structures were identified deep inside atrial myocytes (AMs). Upon excitation, ATs rapidly activate intracellular Ca2+ release and sarcomeric contraction through extensive AT junctions, a cell-specific atrial mechanism. While AT junctions with the sarcoplasmic reticulum contain unusually large clusters of ryanodine receptor 2 (RyR2) Ca2+ release channels in mouse AMs, it remains unclear if similar protein networks and membrane structures exist across species, particularly those relevant for atrial disease modeling. Objective: To examine and quantitatively analyze the architecture of AT membrane structures and associated Ca2+ signaling proteins across species from mouse to human. Methods and Results: We developed superresolution microscopy (nanoscopy) strategies for intact live AMs based on a new custom-made photostable cholesterol dye and immunofluorescence imaging of membraneous structures and membrane proteins in fixed tissue sections from human, porcine, and rodent atria. Consistently, in mouse, rat, and rabbit AMs, intact cell-wide tubule networks continuous with the surface membrane were observed, mainly composed of ATs. Moreover, co-immunofluorescence nanoscopy showed L-type Ca2+ channel clusters adjacent to extensive junctional RyR2 clusters at ATs. However, only junctional RyR2 clusters were highly phosphorylated and may thus prime Ca2+ release at ATs, locally for rapid signal amplification. While the density of the integrated L-type Ca2+ current was similar in human and mouse AMs, the intracellular Ca2+ transient showed quantitative differences. Importantly, local intracellular Ca2+ release from AT junctions occurred through instantaneous action potential propagation via transverse tubules (TTs) from the surface membrane. Hence, sparse TTs were sufficient as electrical conduits for rapid activation of Ca2+ release through ATs. Nanoscopy of atrial tissue sections confirmed abundant ATs as the major network component of AMs, particularly in human atrial tissue sections. Conclusion: AT junctions represent a conserved, cell-specific membrane structure for rapid excitation-contraction coupling throughout a representative spectrum of species including human. Since ATs provide the major excitable membrane network component in AMs, a new model of atrial "super-hub" Ca2+ signaling may apply across biomedically relevant species, opening avenues for future investigations about atrial disease mechanisms and therapeutic targeting.
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    Drosophila Ror is a nervous system-specific co-receptor for Wnt ligands 

    Ripp, Caroline; Loth, Julia; Petrova, Iveta; Linnemannstöns, Karen; Ulepic, Monique; Fradkin, Lee; Noordermeer, Jasprien; Wodarz, Andreas
    Biology Open 2018; 7(11): Art. bio033001
    Wnt ligands are secreted glycoproteins that control many developmental processes and are crucial for homeostasis of numerous tissues in the adult organism. Signal transduction of Wnts involves the binding of Wnts to receptor complexes at the surface of target cells. These receptor complexes are commonly formed between a member of the Frizzled family of seven-pass transmembrane proteins and a co-receptor, which is usually a single-pass transmembrane protein. Among these co-receptors are several with structural homology to receptor tyrosine kinases, including Ror, PTK7, Ryk and MUSK. In vertebrates, Ror-2 and PTK7 are important regulators of planar cell polarity (PCP). By contrast, PCP phenotypes were not reported for mutations in off-track (otk) and off-track2 (otk2), encoding the Drosophila orthologs of PTK7. Here we show that Drosophila Ror is expressed in the nervous system and localizes to the plasma membrane of perikarya and neurites. A null allele of Ror is homozygous viable and fertile, does not display PCP phenotypes and interacts genetically with mutations in otk and otk2 We show that Ror binds specifically to Wingless (Wg), Wnt4 and Wnt5 and also to Frizzled2 (Fz2) and Otk. Our findings establish Drosophila Ror as a Wnt co-receptor expressed in the nervous system.
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    Adults who stutter lack the specialised pre-speech facilitation found in non-stutterers 

    Whillier, Alexander; Hommel, Sina; Neef, Nicole E.; Wolff von Gudenberg, Alexander; Paulus, Walter; Sommer, Martin
    PLOS ONE 2018; 13(10): Art. e0202634
    OBJECTIVES: Persistent developmental stuttering is a speech fluency disorder defined by its symptoms, where the underlying neurophysiological causes remain uncertain. This study examined the underlying neurophysiological mechanisms of the speech planning process, using facilitation in the motor cortex during speech preparation as an analogue. METHODS: transcranial magnetic stimulation (TMS) pulses induced motor evoked potentials (MEPs), which were recorded from the tongue. Eighteen adults who stutter (AWS) and 17 adults who do not stutter (ANS) completed three experiments, which involved reading a German prefix+verb utterance from a screen. Each experiment involved 120 trials with three distinct levels of speech production: immediate speech, delayed speech without pacing and delayed speech with predefined pacing. TMS was applied shortly before speech onset. Trial MEPs were normalised to average non-speech MEPs. MEP amplitude, MEP facilitation ratio (amplitude: pre-speech offset) and group difference were the outcomes of interest analysed by multiple regression, as well as speech reaction time analysed by correlation. RESULTS: MEP values were 11·1%-23·4% lower in AWS than ANS (by standardised Beta), across all three experiments. MEP facilitation ratio slopes were also 4·9%-18·3% flatter in AWS than ANS across all three experiments. Reaction times for AWS were only significantly slower than for ANS in immediate speech and predefined pacing experiments. No stuttering was detected during the trials. The group difference in immediate speech was 100% and 101% greater than the other two experiments respectively. DISCUSSION: While performance of both ANS and AWS worsens under disturbed speech conditions, greater disturbance conditions affected controls worse than AWS. Future research and therapy in stuttering should focus on non-disturbed speech.
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    Training of clinical reasoning with a Serious Game versus small-group problem-based learning: A prospective study 

    Middeke, Angélina; Anders, Sven; Schuelper, Madita; Raupach, Tobias; Schuelper, Nikolai
    PLOS ONE 2018; 13(9): Art. e0203851
    INTRODUCTION: Serious Games are increasingly being used in undergraduate medical education. They are usually intended to enhance learning with a focus on knowledge acquisition and skills development. According to the current literature, few studies have assessed their effectiveness regarding clinical reasoning (CR). The aim of this prospective study was to compare a Serious Game, the virtual Accident & Emergency department 'EMERGE' to small-group problem-based learning (PBL) regarding student learning outcome on clinical reasoning in the short term. METHODS: A total of 112 final-year medical students self-selected to participate in ten 90-minute sessions of either small-group PBL or playing EMERGE. CR was assessed in a formative examination consisting of six key feature cases and a final 45-minute EMERGE session. RESULTS: Overall, the EMERGE group (n = 78) scored significantly higher than the PBL group (n = 34) in the key feature examination (62.5 (IQR: 17.7)% vs. 54.2 (IQR: 21.9)%; p = 0.015). There was no significant difference in performance levels between groups regarding those cases which had been discussed in both instructional formats during the training phase. In the final EMERGE session, the EMERGE group achieved significantly better results than the PBL group in all four cases regarding the total score as well as in three of four cases regarding the final diagnosis and the correct therapeutic interventions. CONCLUSION: EMERGE can be used effectively for CR training in undergraduate medical education. The difference in key feature exam scores was driven by additional exposure to more cases in EMERGE compared to PBL despite identical learning time in both instructional formats. EMERGE is a potential alternative to intensive small-group teaching. Further work is needed to establish how Serious Games enhance CR most effectively.
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    Regenerative glutamate release in the hippocampus of Rett syndrome model mice 

    Balakrishnan, Saju; Mironov, Sergej L.
    PLOS ONE 2018; 13(9): Art. e0202802
    Excess glutamate during intense neuronal activity is not instantly cleared and may accumulate in the extracellular space. This has various long-term consequences such as ectopic signaling, modulation of synaptic efficacy and excitotoxicity; the latter implicated in various neurodevelopmental and neurodegenerative diseases. In this study, the quantitative imaging of glutamate homeostasis of hippocampal slices from methyl-CpG binding protein 2 knock-out (Mecp2-/y) mice, a model of Rett syndrome (RTT), revealed unusual repetitive glutamate transients. They appeared in phase with bursts of action potentials in the CA1 neurons. Both glutamate transients and bursting activity were suppressed by the blockade of sodium, AMPA and voltage-gated calcium channels (T- and R-type), and enhanced after the inhibition of HCN channels. HCN and calcium channels in RTT and wild-type (WT) CA1 neurons displayed different voltage-dependencies and kinetics. Both channels modulated postsynaptic integration and modified the pattern of glutamate spikes in the RTT hippocampus. Spontaneous glutamate transients were much less abundant in the WT preparations, and, when observed, had smaller amplitude and frequency. The basal ambient glutamate levels in RTT were higher and transient glutamate increases (spontaneous and evoked by stimulation of Schaffer collaterals) decayed slower. Both features indicate less efficient glutamate uptake in RTT. To explain the generation of repetitive glutamate spikes, we designed a novel model of glutamate-induced glutamate release. The simulations correctly predicted the patterns of spontaneous glutamate spikes observed under different experimental conditions. We propose that pervasive spontaneous glutamate release is a hallmark of Mecp2-/y hippocampus, stemming from and modulating the hyperexcitability of neurons.
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